A novel lipophilic rhodium catalyst was evaluated in the enantioselective transfer hydrogenation of ketones in water using sodium formate as the hydride donor, and in the presence of sodium docecylsulfonate. Alkyl alkyl ketones were reduced in good yields and in moderate to good enantioselectivities, and the reduction of aryl alkyl ketones proceeded with excellent enantioselectivity (up to 97% ee).

The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures, both of which were developed using solid-phase chemistry. Chapter 1 presents the first of these methods, entailing a practical solid-phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitor the reactions for which a new pulse sequence was developed. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkyl phosphimines or N-aryl phosphimines with reactive alkyl halides.

The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S and K, and the serine protease hepatitis C virus (HCV) NS3 protease. Chapter 4 covers the design, solid-phase synthesis, and structure-activity relationships of 4-amidofurane-3-one P1-containing inhibitors of cathepsin S and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highly potent and selective inhibitors of cathepsin S. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamide inhibitors of cathepsin K are presented in Chapter 5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-like molecules.

The most efficient Ru-catalyzed isomerization–aldol reaction from allylic alcohols has been achieved by using [η5-(Ph5Cp)Ru(CO)2Cl] as the catalyst. The bulky pentaphenylcyclopentadienyl ligand on the ruthenium atom prevents protonation at the oxygen of the Ru–enolate intermediate and completely suppresses the formation of unwanted ketone byproducts (see scheme). The domino transformation is as good as it can be: aldols are obtained in quantitative yields at ambient temperature.

This thesis summarizes three novel and general reaction protocols for the synthesis of diaryliodonium salts. All protocols utilize mCPBA as oxidant and the acids used are either TfOH, to obtain triflate salts, or BF3•Et2O that gives the corresponding tetrafluoroborate salts in situ.

Chapter two describes the reaction of various arenes and aryl iodides, delivering electron-rich and electron-deficient triflates in moderate to excellent yields.

In chapter three, it is shown that the need of aryl iodides can be circumvented, as molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryliodonium triflates.

The final and fourth chapter describes the development of a sequential one-pot reaction from aryl iodides and boronic acids, delivering symmetric and unsymmetric, electron-rich and electron-deficient iodonium tetrafluoroborates in moderate to excellent yields. This protocol was developed to overcome mechanistic limitations existing in the protocols described in chapter two and three.

The methodology described in this thesis is the most general, efficient and high-yielding existing up to date, making diaryliodonium salts easily available for various applications in synthesis.

Diaryliodonium salts have recently received considerable attention as mild arylation reagents in organic synthesis. This paper describes a regiospecific, sequential one-pot synthesis of symmetrical and unsymmetrical diaryliodonium tetrafluoroborates, which are the most popular salts in metal-catalyzed arylations. The protocol is fast and high-yielding and has a large substrate scope. Furthermore, the corresponding diaryliodonium triflates can conveniently be obtained via an in situ anion exchange.

The first part of this thesis describes the synthesis of enantiopure secondary alcohol derivatives. These syntheses are carried out via the combination of an enzyme as a resolution catalyst and a ruthenium catalyst as a racemization catalyst, in what is called dynamic kinetic resolution (DKR). By varying the resolution catalyst enantio-complementary processes can be obtained. A lipase (PS-C II) catalyzed DKR of γ-hydroxyamides gave the corresponding (R)-acetates in high yields and with high enantioselectivity. The synthetic usefulness of these obtained (R)-acetates was demonstrated by the synthesis of (R)-5-methyltetrahydrofurane-2-one. A protease (Subtilisin Carlsberg) catalyzed DKR of various secondary alcohols gave the corresponding (S)-acetates in high yields and with high enantioselectivity. In the second part of this thesis the DKR process has been extended into a dynamic kinetic asymmetric transformation (DYKAT) of diols. Various 1,5- and 1,4-diols were transformed into enantiopure diacetates in a lipase (CALB and PS-C II) catalyzed DYKAT. The synthetic utility of the obtained enantiopure diacetates were demonstrated by the synthesis of various enantiopure disubstituted heterocycles.

26.

Covarrubias, Adrian Suarez

et al.

Department of Cell and Molecular Biology, Uppsala University, Sweden.

Högbom, Martin

Department of Cell and Molecular Biology, Uppsala University, Sweden.

Bergfors, Terese

Department of Cell and Molecular Biology, Uppsala University, Sweden.

Carroll, Paul

Institute for Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London.

Threonine biosynthesis is a general feature of prokaryotes, eukaryotic microorganisms, and higher plants. Since mammals lack the appropriate synthetic machinery, instead obtaining the amino acid through their diet, the pathway is a potential focus for the development of novel antibiotics, antifungal agents, and herbicides. Threonine synthase (TS), a pyridoxal-5-phosphate-dependent enzyme, catalyzes the final step in the pathway, in which L-homoserine phosphate and water are converted into threonine and inorganic phosphate. In the present publication, we report structural and functional studies of Mycobacterium tuberculosis TS, the product of the rv1295 (thrC) gene. The structure gives new insights into the catalytic mechanism of TSs in general, specifically by suggesting the direct involvement of the phosphate moiety of the cofactor, rather than the inorganic phosphate product, in transferring a proton from C4' to C(gamma) in the formation of the alphabeta-unsaturated aldimine. It further provides a basis for understanding why this enzyme has a higher pH optimum than has been reported elsewhere for TSs and gives rise to the prediction that the equivalent enzyme from Thermus thermophilus will exhibit similar behavior. A deletion of the relevant gene generated a strain of M. tuberculosis that requires threonine for growth; such auxotrophic strains are frequently attenuated in vivo, indicating that TS is a potential drug target in this organism.

Highly enantioselective, amino acid-catalyzed, one-pot three-component asymmetric Mannich reactions between dihydroxyacetone, p-anisidine, and aldehydes are presented. The reactions proceeded with high chemo- and stereoselectivity and furnished the corresponding α,α′-dihydroxy-β-aminoketones in high yields with 82–95% ee.

A highly enantioselective catalytic route to protected β-amino-α-hydroxy acids, such as the side chain of Taxotere, is presented. The organocatalytic asymmetric reactions between unmodified protected α-oxyaldehydes and N-Boc-protected aryl imines give the corresponding compound with up to >19:1 dr and 99–99% ee.

In nature, lipases (EC 3.1.1.3) catalyze the hydrolysis of triglycerides to form glycerol and fatty acids. Under the appropriate conditions, the reaction is reversible, and so biotechnological applications commonly make use of their capacity for esterification as well as for hydrolysis of a wide variety of compounds. In the present paper, we report the X-ray structure of lipase A from Candida antarctica, solved by single isomorphous replacement with anomalous scattering, and refined to 2.2-Å resolution. The structure is the first from a novel family of lipases. Contrary to previous predictions, the fold includes a well-defined lid as well as a classic α/β hydrolase domain. The catalytic triad is identified as Ser184, Asp334 and His366, which follow the sequential order considered to be characteristic of lipases; the serine lies within a typical nucleophilic elbow. Computer docking studies, as well as comparisons to related structures, place the carboxylate group of a fatty acid product near the serine nucleophile, with the long lipid tail closely following the path through the lid that is marked by a fortuitously bound molecule of polyethylene glycol. For an ester substrate to bind in an equivalent fashion, loop movements near Phe431 will be required, suggesting the primary focus of the conformational changes required for interfacial activation. Such movements will provide virtually unlimited access to solvent for the alcohol moiety of an ester substrate. The structure thus provides a basis for understanding the enzyme's preference for acyl moieties with long, straight tails, and for its highly promiscuous acceptance of widely different alcohol and amine moieties. An unconventional oxyanion hole is observed in the present structure, although the situation may change during interfacial activation

The highly chemo- and enantioselective organocatalytic tandem reaction between N-carbamate-protected hydroxylamines and a,p-unsaturated aldehydes is presented. The reaction represents a unique entry for the asymmetric synthesis of 5-hydroxyisoxazolidines, oxazolidin-5-ones or gamma-hydroxyamino alcohols in high yields and 90-99% ee. A procedure for the conversion of the oxazolidin-5-ones into the corresponding beta-amino acids is also described.

Four different catalytic systems were studied for biomimetic coupled oxidations using H2O2 or O2. In the first example, osmium tetroxide works as a substrate-selective catalyst for dihydroxylation of olefins. Electron transfer to H2O2 is facilitated by electron transfer mediators (ETMs). In one case VO(acac)2 or MeReO3 was used as ETM; in the other case a combination of flavin and tertiary amine was used as ETMs. These three systems were immobilized in the ionic liquid [bmim]PF6 for the purpose of recycling of the catalyst.

In the second example, an organocatalyst (a flavin) was used for the oxidation of sulfides to sulfoxides and this catalytic system was recycled and reused in an ionic liquid.

In the third example, primary aromatic amines were oxidized by H2O2 to nitroso compounds in a selenium-catalyzed oxidation. The nitrosoarenes were used in a one-pot hetero Diels-Alder reaction with dienes forming 1,2-oxazines.

In the fourth example, a cobalt salophen complex was immobilized in different zeolites. The catalyst was used in aerobic oxidation of p-hydroquinone and the zeolite catalyst could be reused. The oxidative carbocyclization of ene-allenes was tested successfully using the triple catalytic system consisting of palladium(II), p-benzoquinone, and the immobilized catalyst for O2 activation.

All these systems gave mild and selective oxidations with environmentally friendly and inexpensive terminal oxidants.